Historical Development of Muscle Energetics

The lactic acid theory and its disproof: Experiments at the beginning of the 20th century were directed to find the chemical substance that provides the energy for muscle contraction. The procedure was as follows: One of the two gastrocnemius muscles of a frog was stimulated till fatigue, while the other muscle was resting. Both muscles were analyzed for their chemical constituents. In the stimulated muscle the lactic acid content was increased, its formation was equivalent to the glycogen breakdown. Based on this type of experiments, it was postulated that the energy for contraction was provided by glycolysis that is the breakdown of glycogen to lactic acid:

This was called the Lactic Acid Theory. However, Lundsgaard showed in 1930 that lactic acid production is not essential for muscle contraction. He injected one of two frogs with iodoacetate (IA), stimulated one muscle of both frogs to perform a certain amount of work while the other muscle of both frogs was resting (Fig. EN1).

Fig. EN1. The Lundsgaard experiment. (From Needham, 1971). Tension records. Upper curve: Contraction of normal muscle. Lower curve: IA-poisoned muscle.

In the IA-injected frog, in which glycolysis was inhibited, the lactic acid content was very small, it was the same in the working and resting muscle; importantly, the phosphocreatine was completely used up in the working muscle (Table EN2) . On the other hand, in the control frog, lactic acid production increased about 3-fold in the working muscle (as compared to the resting muscle) whereas the phosphocreatine decreased only slightly. Based on these type of experiments, the Lactic Acid Theory was ruled out and it was suggested that phosphocreatine may be the immediate energy source of muscle contraction.

Tab. EN2. Chemical analyses of the muscles from the Lundsgaard experiment, shown on Fig. EN1. Values correspond to mg lactic acid/g muscle and mg PCr/g muscle.

The Lohmann reaction and its inhibition: In 1934, Lohmann showed that in muscle extracts, ATP and PCr were held in equilibrium by a specific enzyme now known as creatine kinase (Equations, EN3):

creatine

PCr - phosphocreatiisft Cr - crsaiine

Ths equilibrium cgnscant of îhis ration is

[ATP] iCrJ

Equ. EN3. The Lohmann reaction.

Since the equilibrium constant is greatly shifted toward ATP formation and not toward PCr formation, the results indicated that PCr might not be the immediate energy source for muscle contraction. This conclusion was substantiated by the lack of an enzyme in muscle that would hydrolyze PCr into Cr and Pi. The results also indicated that ATP might be the immediate energy source; demonstration of this required the inhibition of creatine kinase.

Almost 30 years have passed until Cain and Davies (1962) were able to inhibit creatine kinase in frog muscle with 1-fluoro-2.4-dinitrobenzene (FDNB) and thereby measured the decrease in ATP concentration during contraction (Table, EN4). This provided the proof that ATP is the direct energy source for contraction. Without inhibiting creatine kinase, decrease in ATP concentration could not be measured because the formed ADP was immediately rephosphorylated to ATP via the creatine kinase (Lohmann) reaction. As a matter of fact, during contraction of normal muscle, the ATP concentration remains fairly constant while the PCr concentration decreases.

Single contraction 0,81 0.90

Table EN4. ATP breakdown in FDNB-treated muscle. (Cain and Davies, with permission from Biochem. Biophys. Res. Commun.,1962, Academic Press). Values in |moles/g wet weight muscle.

Single contraction 0,81 0.90

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